MEK/ ERK and signal transducer and activator of transcription signaling pathways modulate oncostatin M- stimulated CCL2 expression in human osteoblasts through a common transcription factor.
OBJECTIVE: To analyze the effects of oncostatin M (OSM), a gp130-type cytokine, on CCL2 expression in MG-63 cells, a human osteosarcoma cell line with a characteristic osteoblastic phenotype, and to investigate the signaling pathway involved. METHODS: The expression of messenger RNA (mRNA) for CCL2 and c-Fos was analyzed by Northern blotting. Amounts of CCL2 released into the supernatant were measured by enzyme-linked immunosorbent assay. Western blotting was used to examine the activation of MAPK signaling pathways. Interactions between activator protein 1 (AP-1) and DNA were evaluated by electrophoretic mobility shift assay. RESULTS: OSM stimulated CCL2 expression at both the mRNA and the protein levels. Cyclooxygenase 2 ( COX-2) was also induced by OSM. However, the up-regulation of CCL2 mRNA was COX-2-independent but required tyrosine kinase and protein kinase C (PKC). OSM stimulated the phosphorylation of MEK-1/2 and ERK-1/2 but not p38 and JNK. A transient elevation of c-Fos mRNA was induced by OSM, but PD 98059 (MEK inhibitor), fludarabine (signal transducer and activator of transcription 1 [STAT-1] inhibitor), and piceatannol (STAT-3 and STAT-5 inhibitor) abolished this effect. Electrophoretic mobility shift assay revealed that OSM stimulated AP-1-DNA binding, which was also abolished by PD 98059, fludarabine, and piceatannol. Supershift study further confirmed the role of c-Fos in the above interaction. PD 98059, fludarabine, piceatannol, and curcumin (AP-1 inhibitor) inhibited the OSM- induced expression of CCL2. CONCLUSION: OSM induces CCL-2 expression in osteoblasts. Activation of the MEK/ ERK and STAT pathways, which leads to c-Fos expression and AP-1-DNA binding, is involved in the process. The signaling requires tyrosine kinase and PKC but not COX-2.[1]References
- MEK/ERK and signal transducer and activator of transcription signaling pathways modulate oncostatin M-stimulated CCL2 expression in human osteoblasts through a common transcription factor. Lin, S.K., Kok, S.H., Yeh, F.T., Kuo, M.Y., Lin, C.C., Wang, C.C., Goldring, S.R., Hong, C.Y. Arthritis Rheum. (2004) [Pubmed]
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